ADP-ribosylation, in which the ADP-ribose moiety of NAD is transferred to a target protein, is catalyzed by a family of bacterial toxins and mammalian enzymes. Some toxin transferases appear to be responsible for the diseases caused by the bacterium. The mammalian enzymes are located both within the cell and on the cell surface, sometimes, linked through a glycosylphosphatidylinositol anchor. Other mammalian transferases apppear to be secreted. A family of the mammalian enzymes have been cloned in the laboratory. Of note, these enzymes are specifically expressed in cells involved in the inflammatory response.The presence of NAD-metabolizing enzymes (e.g., ADP-ribosyltransferase (ART)1) on the surface of immune cells suggests a potential immunomodulatory activity for ecto-NAD or its metabolites at sites of inflammation and cell lysis where extracellular levels of NAD may be high. In human airways, epithelial cells lining the lumen and intraluminal cells (e.g., polymorphonuclear cells) participate in the innate immune response and secrete or have on their surface NAD:arginine ADP-ribosyltransferases. Defensins, antimicrobial peptides secreted by immune cells, are arginine-rich, leading to the hypothesis that ADP-ribosylation could modify their biological activities. The group found that ART-1 modifies arginine-14 of alpha-defensin-1. ADP-ribosylated defensin-1 had decreased cytotoxic and antimicrobial activities but still stimulated T-cell chemotaxis and IL-8 release from A549 cells. In addition, ADP-ribosylated defensin inhibited the cytotoxic and antimicrobial activities of unmodified defensin-1. ADP-ribosylated defensin-1 was identified in bronchoalveolar lavage fluid from smokers, but not from nonsmokers, confirming its existence in vivo. Thus, airway NAD:arginine ADP-ribosyltransferases could have an important regulatory role in the innate immune response through modification of alpha defensin-1, and perhaps other cationic molecules, with alteration of their biological properties. These data suggest that ADP-ribosylation may be involved in modulating the innate immune response.